PatientsTwenty-nine eyes of 15 patients with XLRS receiving treatment with the topical dorzolamide formulation for 4 to 41 months were enrolled.

Main Outcome MeasuresChanges in visual acuity, cystic macular lesions, and central foveal zone thickness on optical coherence tomography during follow-up for the duration of treatment.

ResultsAmong the 15 patients with XLRS, 20 eyes (69%) of 11 patients showed a positive response to treatment. Five of the 20 eyes (25%) in 3 of the 11 patients showed an initial response and a subsequent rebound of macular cysts. In 4 eyes (14%) of 3 patients, there was no response to treatment, but the macular cysts did not worsen compared with the baseline level. In 5 additional eyes (17%) of 4 patients, there was no response to treatment, and the macular cysts worsened when compared with the baseline level. Sixteen eyes (55%) of 12 patients had improvement in best-corrected visual acuity by at least 7 letters in at least 1 eye at the most recent follow-up visit. Seventeen eyes (59%) of 10 patients showed a reduction in the central foveal zone thickness in at least 1 eye when compared with the pretreatment level.

ConclusionPatients with XLRS have the potential to experience a beneficial effect from sustained treatment with dorzolamide, 2%.

Figures in this Article

Juvenile X-linked retinoschisis (XLRS) is a relatively rare hereditary retinal disease with an estimated prevalence ranging from 1 in 15 000 to 1 in 30 0001 and is caused by mutations in the RS1 gene (MGI 1336189; OMIM +312700) on Xp22,2 which leads to splitting of the neural retina and reduced visual acuity (VA) in affected male patients. It is the most common cause of juvenile-onset macular degeneration in male patients. The patients typically have a cystlike stellate maculopathy or foveal schisis.2- 5 Affected individuals have a reduction in central vision that typically is observed between 5 and 10 years of age.3,5 Visual impairment is usually mild and generally stable until the fourth or fifth decade of life, when progressive visual deterioration often occurs. However, less commonly, patients with XLRS may have a squint, nystagmus, and bilateral, highly elevated bullous retinoschisis, often with hemorrhage within the schisis cavity or into the vitreous, in early infancy.5,6 Other findings that may occur, generally in later stages of XLRS, include vitreous hemorrhage, chorioretinal atrophy, and retinal detachment.6 Although not always present, a distinctive feature of this disease is a selective or predominant b-wave amplitude reduction shown on full-field electroretinography.7 Retinal morphological changes in patients with XLRS undergoing evaluation with high-speed, high-resolution Fourier-domain optical coherence tomography (OCT) reveal the presence of foveal schisis involving the outer and inner plexiform layers and disruption and irregularity of the photoreceptor outer and inner segment layers.8

Carbonic anhydrase inhibitors (CAIs) have been used clinically for several years to lower intraocular pressure (IOP).9 Recently, their use has been shown to be effective for the improvement of cystoid macular edema (CME) in patients with several retinal diseases such as retinitis pigmentosa10- 12 and uveitis13 and when CME is found in conjunction with epiretinal macular membranes.14 Topical and oral forms of CAIs have also been demonstrated to cause an improvement in the macular cystlike cavities in some cases of XLRS, as documented by OCT and an improvement in VA.15- 17

Although previous studies have shown a beneficial effect from the use of a topical CAI in patients with XLRS,15,17 these studies had a limited number of patients followed up for a short period. Therefore, the aim of the present study was to determine the efficacy for sustained use of topical dorzolamide hydrochloride, 2%, on VA and foveal cystlike lesions, as determined by OCT, in patients with XLRS.

METHODS

PARTICIPANTS

This was an observational retrospective case series study. All patients 18 years or older with XLRS who were treated with the topical dorzolamide formulation from September 19, 2005, through March 20, 2009 (range, 4-41 months), in the Department of Ophthalmology at the University of Illinois at Chicago were enrolled in the study. The study was conducted in accordance with the ethical standards stated in the 1964 Declaration of Helsinki and was approved by an institutional review board at the University of Illinois at Chicago.

Twenty-nine eyes of 15 patients with XLRS were included, and informed consent was obtained from all participants. Inclusion criteria consisted of juvenile XLRS and stable ocular fixation with no clinically significant media opacities. Exclusion criteria consisted of a refractive error greater than ±6 diopters (D) sphere, uveitis, optic neuropathy, the presence of nystagmus or any other retinal diseases affecting the macula other than retinoschisis, a history of glaucoma or increased IOP of at least 21 mm Hg, a history of intraocular surgery, and poor OCT image quality.

All subjects underwent a complete ocular examination, including best-corrected VA (BCVA) with the use of an Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Lighthouse, Long Island City, New York). On the basis of previous studies,15,18 the authors determined that an increase of at least 7 letters on an ETDRS chart would be considered a significant change in VA. Slitlamp biomicroscopic examinations and IOP measurements with Goldmann applanation tonometry were performed on all patients. Dilated fundus examinations were performed using direct and indirect ophthalmoscopy and stereoscopic biomicroscopy with a noncontact +78-D lens. None of the subjects included in the study had been treated with systemic or topical corticosteroids, thiazide diuretics, or nonsteroidal anti-inflammatory drugs. Also, none of the patients had taken an oral or a topical form of CAI before its use in this study.

OCT EXAMINATION PROTOCOLS

All subjects included in the study underwent OCT examinations at each visit to monitor the changes in their macular cysts using a time-domain system (TD-OCT) (Stratus OCT, with software version 4.0.1; Carl Zeiss Meditec Inc, Dublin, California) or a spectral-domain system (SD-OCT) (RTvue, with software version 3.5; Optovue Inc, Fremont, California).

The following examination protocols were used for monitoring the macular cystic changes. In the TD-OCT system, we used the macular thickness scan protocol, which consisted of 6-mm radial scans acquired sequentially at 30° polar intervals, passing through the center of the fovea. The total acquisition time was 11.76 seconds. Each radial scan consisted of 512 A-scans. For the SD-OCT system, we used the MM5 and radial lines protocols, in which the radial scan consisted of twelve 6-mm radial scans at 15° polar intervals passing through the center of the fovea. All 12 scans were acquired simultaneously, and the total acquisition time was 0.27 seconds. Each radial line consisted of 1024 A-scans. The MM5 scan protocol consisted of a raster protocol of 5 × 5 mm centered at the fovea, with a total acquisition time of 0.78 seconds.

DATA ANALYSIS

Qualitative Analysis

The overall response and nonresponse to treatment in all of the study patients were evaluated separately in a qualitative manner by two of us (M.A.G. and G.A.F.) and were graded as improvement, improvement with a subsequent rebound, no improvement, and no improvement with worsening of the macular cysts. In addition, we assessed the degree of the response to treatment, which was graded as no response, improvement (mild, moderate, or marked), and worsening (mild, moderate, or marked). Moreover, the foveal cyst sizes based on OCT examinations on initial and most recent visits were qualitatively graded as no cyst (0), small cysts (1), moderate cysts (2), or large cysts (3).

Quantitative Analysis

Changes in the central foveal zone (CFZ) thickness, which was defined as the central 1000 μm centered on the foveola, were used to monitor the response to treatment. A change in the CFZ thickness from the baseline level (pretreatment) of greater than 17.1% (mean [2 SDs]) was used as a statistically significant intervisit change as reported previously.15

The macular thickness data obtained by SD-OCT were compared with normative data provided to us by the manufacturer that were not corrected for age and optic disc size and that were retrieved from 268 eyes of 134 normative control subjects (mean [SD] age, 44.1 [15.5] years; mean [SD] foveal thickness, 265.8 [23.9] μm). The paired t test was used to statistically analyze mean CFZ thickness and logMAR VAs. P < .05 was considered statistically significant. Unless otherwise indicated, data are expressed as mean (SD).

RESULTS

We analyzed data on 29 eyes, including 14 right eyes (48%) and 15 left eyes (52%), from 15 patients with XLRS. In 1 patient (7%), only 1 eye was included owing to the presence of rotatory nystagmus. There were 12 white (80%) and 3 Hispanic patients (20%) enrolled in the study. In 8 patients (53%), the abnormal disease-causing gene mutations were previously identified (Table 1).

The mean age of the patients at their initial baseline visit was 31.9 (10.5) (median, 32; range, 18-53) years. The mean age at the most recent follow-up visit was 33.7 (10.5) (median, 32; range, 19-54) years. The average number of visits was 6.8 (3.6) (median, 5; range, 3-14) (Table 1). The overall mean duration of follow-up was 16.5 (13.8) (median, 8; range, 4-41) months. Three patients (20%) were followed up for less than 6 months, with a mean follow-up of 4.3 (0.5) months; 5 patients (33%), from 6 to 12 months, with a mean follow-up of 6.6 (0.8) months; and 7 patients (47%), for more than 12 months, with a mean follow-up of 28.7 (10.0) months (Table 2).

On their most recent follow-up visit while receiving treatment with topical dorzolamide, 6 patients (40%) reported a subjective improvement in their central vision.

Among our 15 study patients, 16 eyes (55%) of 12 patients (80%) had improvement in their BCVA by at least 7 letters on an ETDRS chart in at least 1 eye at the most recent follow-up visit. Regarding the 14 right eyes, 8 patients (57%) had improvement in their BCVA by at least 7 letters on an ETDRS chart at the most recent follow-up visit. Six patients (43%) did not show significant improvement in their BCVA. Among these 6, 1 patient did not have a change from the initial baseline (pretreatment) level, whereas 5 patients showed a minimal decrease in their BCVA from 1 to 4 letters on an EDTRS chart (0.02-0.08 logMAR) when compared with their baseline level. Regarding the 15 left eyes, 8 patients (53%) showed an improvement in their BCVA by at least 7 letters on an ETDRS chart at the most recent follow-up visit, whereas 7 patients (47%) had gained less than 7 letters at their most recent visit. Among these 7, 1 patient had no change from the initial baseline level, and 2 had gained only 1 or 4 letters on an ETDRS chart (0.02 or 0.08 logMAR). The other 4 patients had a minimal decrease in their BCVA of from 1 to 5 letters on an ETDRS chart (0.02-0.10 logMAR) when compared with their baseline level.

All 15 study patients showed initial evidence of macular cysts diagnosed by means of direct ophthalmoscopy, biomicroscopy, and OCT. At their most recent visit, 13 patients (87%) still showed evidence of macular cysts, although the cystic cavities were smaller in 11 patients and unchanged in 2.

At the initial baseline visit, 3 patients (20%) had their macular schisis measured by the SD-OCT and 12 patients (80%) by TD-OCT. At the most recent follow-up visit, 8 patients (53%) had their macular schisis measured by SD-OCT and 7 patients (47%) by TD-OCT.

Regarding the frequency of the administration of the topical dorzolamide hydrochloride, 2%, all 15 study patients were prescribed the topical drops at a frequency of 3 times a day in both eyes. In 5 patients (33%), the frequency was decreased to twice a day after a mean period of 7.6 (1.5) (median, 7) months in both eyes owing to continued improvement in the thickness of their macular cysts.

At the most recent follow-up visits among our XLRS cohort, 20 eyes (69%) (from 11 patients [73%]) had an improvement on OCT findings in the degree of macular cystic changes after treatment. Nine patients (60% of the total number) showed a positive response to treatment in both eyes, and 2 patients (13%) showed a positive response to treatment in 1 eye. Five of the 20 eyes (25.0%) (from 3 patients [20%]) showed an initial response to treatment and a subsequent worsening of their CME based on OCT evaluation during a mean period of 10.6 (7.2) (median, 6.0) months owing to a decrease in the frequency of treatment administration from 3 times a day to twice a day (3 eyes) or owing to poor patient adherence to treatment (2 eyes) (Figure 1). On follow-up of these 5 eyes, 3 (60%) eventually had a positive response to treatment after the dosage was increased again from twice a day to 3 times a day, whereas 2 eyes (40%) continued to show no response to continued treatment 3 times a day, partially owing to poor patient adherence to treatment.

Our data showed that 4 eyes (14%) (from 3 patients [20%]) did not show any response to treatment, although the macular cysts did not worsen when compared with the pretreatment level. In addition, 5 eyes (17%) (from 4 patients [27%]) showed no response to treatment and the macular cysts worsened when compared with the pretreatment level. The degree of worsening was moderate according to the qualitative method of evaluation (Figure 2).

Among the 20 eyes that showed a degree of response to treatment during the follow-up, 15 eyes (75%) showed a sustained improvement from treatment throughout the entire follow-up period (mean, 16.5 [13.8] months). Among these 15 eyes, 8 (53%) showed a sustained improvement with treatment twice a day.

The overall mean CFZ thickness at the initial baseline visit was 391.9 (115.2) μm, whereas it was 296.4 (134.0) μm at the most recent follow-up visit (P = .008). When we used the criterion of a change in the CFZ thickness from pretreatment of greater than 17.1% (mean [2 SDs]) as a statistically significant intervisit change, as previously reported,15 17 eyes (59%) (from 10 patients [67%]) showed more than a 17.1% decrease in the CFZ thickness from the initial baseline (pretreatment) level in at least 1 eye (Table 5).

COMMENT

Topical and oral forms of a CAI have been demonstrated to cause a reduction in the cystic macular lesions in some cases of XLRS, as documented by OCT, and an improvement in VA.15- 17 Our study also demonstrates that the changes in VA and apparent macular cystic changes on OCT did not correlate with the clinically evident macular cystic changes in the fundus. Clinically evident improvement in the cystic macular lesions was often less apparent than improvement on OCT measurements, and modest improvement of only 1 line in VA was observed even with appreciable improvement in cystic changes on OCT. We also noted that individual patients did not reach their full potential to respond to treatment until after a period of up to 5 months. Previous reports had shown that the cystic macular lesions in XLRS may spontaneously resolve, followed by the development of an atrophic lesion in the macula.5,6 Hence, it is likely important to treat the macular cysts found in patients with XLRS to possibly reduce the occurrence of later-onset atrophic macular lesions.17

Our study demonstrated that 20 eyes (69%) of 11 patients had a positive response to treatment with the topical dorzolamide formulation, which was evident by an improvement of the cystic macular lesions on OCT. Our finding agrees with previous reports by Apushkin and Fishman15 and Ghajarnia and Gorin,16 which described similar positive effects on the cystic macular lesions when treated with a CAI. Also, 6 patients (40%) in our study group noticed subjective improvement in their central vision described as images becoming distinctly brighter after the use of the treatment for at least 2 months. Significant improvement in BCVA was noted in 8 patients (57%) in their right eyes, whereas the left eyes of 8 patients (53%) demonstrated a gain in VA of at least 7 letters on an ETDRS chart at the most recent follow-up visit during a mean period of 18.1 (15.2) months.

In our study, 5 eyes (17%) of 4 patients showed no response to treatment, and the macular cysts worsened, as noted on results of the clinical fundus and OCT examinations. An explanation for this finding is not clearly apparent. It may be related to different genetic mutations causing different mechanisms of retinoschisin protein dysfunction. It may also depend on the residual function of the retinal pigment epithelial cells in individual patients because a CAI has been shown to affect the pumping mechanism in these cells.20- 23 It would be reasonable to conduct a future study that correlates the genotype in patients with XLRS with a response to treatment with the study formulation of dorzolamide.

One of the interesting findings in our study was that, among the 20 eyes that showed a favorable response to treatment, 15 showed sustained improvement in their macular cysts through the entire follow-up, whereas 5 eyes showed a rebound in macular cysts during which the CFZ thickness and extent of the cysts on OCT returned to at least baseline levels. On follow-up of these 5 eyes, 3 again showed a notable improvement with continued treatment after the dosage was increased from twice a day to 3 times a day. These findings suggest that patients with XLRS who are receiving dorzolamide be monitored for a potential rebound of their macular cysts or a lack of response during treatment.

One limitation of the study was that the normative data for macular thickness provided by the manufacturer for the SD-OCT system was not corrected for age. Also, some patients were initially followed up with TD-OCT and subsequently underwent SD-OCT. Longitudinal change in CFZ thickness could not be calculated properly because of the difference in the measurements between the 2 systems. However, a previous report by London and Fung24 showed that the differences between the TD- and SD-OCT devices are minimal and not likely to be clinically relevant. Similar findings were also noticed in a recent report by Fullerton et al,25 who stated that the macular thickness measurements obtained by TD-OCT were consistently lower but highly correlated with those obtained by SD-OCT. The highest correlation was observed in the central 1-mm foveal region.

From our experience, we suggest the following guidelines for using dorzolamide eyedrops, 2%, in patients with XLRS who have cystlike cavities. Perform a baseline ocular examination, including VA measurement and OCT, and begin therapy with dorzolamide hydrochloride, 2%, 3 times a day in both eyes; follow up after 2 months with clinical and OCT examinations. If there is improvement in the CFZ thickness on OCT, continue to use the eyedrops 3 times a day for another 2 months. If after 4 months the CFZ thickness on OCT shows sustained improvement, the dosage can be decreased to twice a day. The patient should be followed up again in 2 months to look for a sustained response or a rebound. If the CFZ thickness on OCT shows a rebound of the macular schisis, increase the dosage back to 3 times a day. If after 6 months there is still a favorable response on a dosage of twice a day or 3 times a day, continue to use the eyedrops twice a day or 3 times a day. However, if no response is noted or a rebound is noted after 6 months of treatment with eyedrops 3 times a day, discontinue use of the eyedrops. These suggested guidelines may be expanded or modified as more experience is accrued on a larger number of patients with an even longer follow-up.

Additional suggestions include the recommendation to continue the use of topical dorzolamide, even when there is no notable initial response, because some patients with XLRS may not show a clinically significant response until after treatment for up to 5 months. It is vital to ascertain whether patients are adhering to their medication regimens and are instilling the drops properly.

Although not all patients will respond to dorzolamide, our study determined that patients with XLRS can maintain a beneficial effect from sustained treatment with a topical form of CAI such as dorzolamide, 2%.

Submitted for Publication: June 16, 2009; final revision received September 9, 2009; accepted September 26, 2009.

Financial Disclosure: None reported.

Funding/Support: This study was supported by funds from the Foundation Fighting Blindness, Grant Healthcare Foundation, core grant EYO1792 from the National Institutes of Health, and an unrestricted departmental grant from Research to Prevent Blindness.

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